An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223

Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established.

The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy.

Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively.

Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.

Annals of oncology : official journal of the European Society for Medical Oncology. 2017 May 01 [Epub]

O Sartor, R E Coleman, S Nilsson, D Heinrich, S I Helle, J M O'Sullivan, N J Vogelzang, Ø Bruland, S Kobina, S Wilhelm, L Xu, M Shan, M W Kattan, C Parker

Departments of Medicine and Urology, Tulane Cancer Center, New Orleans, USA., Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Sheffield, UK., Department of Oncology, Karolinska University Hospital, Stockholm, Sweden., Department of Oncology, Akershus University Hospital, Lørenskog., Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway., Department of Clinical Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland., Department of Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, USA., Department of Medical Oncology and Radiotherapy, University of Oslo, Norwegian Radium Hospital, Oslo, Norway., Oncology Global Medical Affairs, Bayer HealthCare Pharmaceuticals, Whippany., Infinity Analytics Group Inc, Madison., Department of Statistics, Oncology, Bayer HealthCare Pharmaceuticals, Whippany., Quantitative Health Sciences, Cleveland Clinic, Cleveland, USA., Academic Urology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, UK.